The long-term goal of my studies is to elucidate the early events in the genetic program conducive to meiotic cell fate determination in metazoans using Drosophila melanogaster-the metazoan model organism in which I will be trained during the mentored phase of this award. I will start my research by investigating IME2 and IME4, two highly conserved genes that have been shown to be required for meiosis in S. cerevisiae. The understandig of the genetic program that determines meiotic cell fate will provide insight into understanding infertility and the consequences of dysfunction of the mitotic:meiotic switch. Both IME2 and IME4 have homologs in mice, rats, and humans. Specific aims: The specific aims of this proposal span both the two-year mentored phase of this award in which I will train in D. melanogaster's husbandry, genetics, molecular genetics and cytological techniques to investigate the role of IME4 and IME2 in meiosis, and the three year independent phase of this award in which I will further pursue my findings and establish myself as an independent investigator: Phase I: Aim 1: To create mutants of ime4 and ime2 in D. melanogaster by classical genetics and RNAi knock-downs and initiate their phenotypic characterization. Aim 2: To study the specific roles of Ime4 and Ime2 in oogenesis and spermatogenesis. Phase II: Aim 3: To investigate the role of Ime4 as an RNA methyltransferase in gametogenesis and identify its targets for this modification. Aim 4: To determine the role of Ime2 as a kinase in gametogenesis and identify its substrates. Relevance to public health: Male and female germ cells commit some of its cells to reduce by half their chromosomal content to become sperm and egg respectively by a specialized cell division called meiosis. The early factors that determine commitment to meiosis are not known. My proposed experiments are aimed at elucidatng the genetic program that makes a germ cell enter meiosis. My findings will provide information to understand infertility and the role of proper function of the mitosis:meiosis switch whose dysfunction has been suspected in some germline cancers.